1. Field of the Invention
This invention relates to a diagnostic and therapeutic 1-[2-(diarylmethoxy) alkyl]-4-(3-aryalkyl) piperazines and piperidines, their use as diagnostic or therapeutic agents and to a process for making the piperazines and piperidines.
2. Description of Prior Art
The dopaminergic (DA) neurotransmitter systems are intimately involved with a number of central nervous system (CNS) disorders including those involved with movement, e.g., Parkinson""s Disease and reinforcing effects, e.g., cocaine dependency. Interest in these two disorders in particular has stimulated research efforts to develop specific agents that can be used either diagnostically, to evaluate the extent of the disease, or therapeutically to antagonize the effect of cocaine. Cocaine recognition sites are localized on dopamine nerve terminals. Drugs that bind, affect or block these sites therefore have potential uses which include: (i) imaging probes for neurodegenerative disorders; and (ii) imaging probes for dopamine transporter/cocaine binding sites. Furthermore, in many instances these compounds or analogs become active on other sites that affect the serotonergic system and, therefore, may be used to treat disorders associated with serotonin (e.g., depression, PMS, weight, psychosis or aging).
Because of the unique anatomical location of the cocaine recognition sites, a high affinity probe for imaging of these sites in vivo in the brain can be carried out using positron emission tomography (PET) or single photon emission computed tomography (SPECT) imaging. Such imaging is useful for diagnosing or monitoring the Parkinson""s disease, other neurological disorders characterized by the degeneration of dopamine nerve terminals or by aging. Preferably, the common target for compounds that would fulfill these objectives is the dopamine transporter (DAT), a 12-transmembrane spanning presynaptic protein that removes the dopamine from the synaptic clef following its release. The two classes of competitive drugs that have been most extensively examined are the stable tropane analogs of cocaine characterized by WIN 35,428 (also known as CFT) and the piperazine derivatives characterized by GBR-12935. Both exert their effect at nanomolar concentrations.
The cocaine analog, 2xcex2-carbomethoxy-3xcex2-(4-fluorophenyl) tropane (CFT) and other analogs have proven to be an effective probe for studying dopamine-related diseases and cocaine binding sites in the striatum. For example, the progression of Parkinson""s disease in primate models and subjects can be monitored by administering radiolabeled analogs of CFT and imaging the distribution of radioactivity in the brain. PET has been used to image 11C labeled analogs of CFT in primate models, Hantraye et al., Neuroreport 3.265 (1992), Farde et al., Synapse 16:93 (1994) while SPECT has been used to image iodinated CFT analogs in both primate models and human subjects (Shaya et al., Synapse 10:169 (1992) and Neumeyer et al., J. Med. Chem. 34:3144 (1991, Elmaleh et al., J. Nucl. Med.
Various substances (particularly cocaine and cocaine congeners) are potent inhibitors of dopamine transport in the striatum of the brain because they bind to the dopamine transporter. These substances have different affinities or IC50""s for inhibiting dopamine transport and for blocking cocaine. The more strongly these substances block dopamine transport, the more strongly they bind to sites on the dopamine transporter which have been labeled by [3H] cocaine or by [3H] CFT, Madras et al., (1089) J. Pharmacol. Exp. Ther. 251:131-141; and Madras et al. (1989) Mol. Pharmacol. 36:518-524. The hope that these compounds might be Parkinson""s markers is further supported by the parallel between loss of binding and loss of dopamine in the diseased brain (Madras et al., Catechol. Symp. 193, 1992).
Because of its widespread, low cost and simplicity, SPECT is preferred to PET for routine imaging directed towards diagnosis. Technetium-99m is the tracer of choice for SPECT imaging because of its excellent physical characteristics and widespread availability. Recently, technetium-99m CFT analogs were reported which appear to be extracted by the brain and concentrate preferentially in its dopamine rich regions (Madras et al., Synapse 22:239 (1996) and Meegalla et al., J. Am. Chem. Soc. 117:11037 (1995).
There is need for improved diagnostic agents and markers of neurogenerative disorders which have improved specificity for concentrating in dopamine rich regions in the brain. Such agents can provide improved diagnosis for excluding at an early stage of Parkinson""s disease as the cause of symptoms which may be useful information in diagnosing other conditions. Moreover, early diagnosis of Parkinson""s disease can facilitate the introduction of putative prophylactic drug therapy (e.g., deprenyl) prior to the onset of more severe symptoms, Kaufman and Madras (1991) Synapse 9:43-49. Detection of nerve cell depletion in the presymptomatic phase in an animal model of Parkinson""s disease would also be useful, e.g., when using the model to evaluate therapies for Parkinson""s disease, Hantraye et al. (1992) Neurol. Reports 3:26-268; and Hahtraye et al. (1992) Soc. Neurosci. Abstra. 18:935.
There is a particular need for diagnostic agents and markers of neurogenerative disorders that selectively target a domain transporting protein (the dopamine transporter) in preference to another protein known as the serotonin transporter. In normal brain tissue, the dopamine: serotonin transporter density ratio is approximately 10:1. Diagnostic agents can be used to monitor the effects of Parkinson""s disease therapy by determining the loss or reduction of loss of dopamine. In certain neurodegenerative disorders, such as Parkinson""s disease, nerve cells that produce dopamine (and on which the dopamine transporter is located) undergo severe depletion while serotonin transporter ratio can fall to 50% in Parkinson""s disease.
Accordingly, it would be desirable to provide improved diagnostic and therapeutic compositions which have improved selectivity for being concentrated in dopamine regions of the brain as compared to presently available diagnostic and therapeutic compositions. Such improved diagnostic and therapeutic compositions can provide a means for earlier detecting an abnormal condition of the brain measurable by determining the state of the dopamine rich regions. In addition, such improved therapeutic composition can provide a basis for more effective treatment of a patient such as a cocaine-dependent patient. In addition it is desirable to provide a drug that blocks cocaine uptake while allowing dopamine reuptake. Furthermore, drugs which are partial agonists or antagonists can have a useful application.
The present invention is based on the discovery that N-[2-bis[arylmethoxy) alkyl piperazines and piperidines have high affinity and high selectivity for dopamine transporters.
The compounds of this invention are represented by the Formula I and physiologically acceptable salts thereof: 
wherein:
A is oxygen or nitrogen; n is an integer of 2 to 6; X and Y can be the same or different and are hydrogen, halogen, nitro, alkyl or halalkyl, Z is carbon or nitrogen; and xcfx86 is phenyl, naphthyl, thienyl or pyridinyl.
When Z is carbon, R is hydrogen, cyano, hydroxy, xe2x80x94COOCH3, xe2x80x94CH2OH or xe2x80x94COOH; R1 is 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethyl-3-chlorophenyl, 4-bromophenyl, 4-(2-keto-1-benzimidazolinyl or 1-phenyl-1, 3, 8-triazaspiro [4,5] decan-4-one. When Z is nitrogen, R and R1 combined are 
wherein R3 is halo, alkyl, cyano or nitro and R2 can be hydrogen or 
wherein R4 is halo, alkyl, cyano, nitro, alkylnyl or alkenyl.
The compounds of this invention are useful as diagnostic agents in their labeled form with radionuclides such as 123I, 125I, 99mTc or the like. In their labeled or unlabeled form, the compounds of this invention are useful as therapeutic acceptable carrier. Such compositions can be used to selectively image cocaine binding regions of the central nervous system of a human patient by administering detectably labeled compound of this invention to the central nervous system and detecting the binding of that compound to CNS tissue by (PET) or (SPECT). Such a compound also are useful in treatment of neurodegenerative disorders characterized by dopamine deficits or cocaine abuse and to follow the effects of therapy for dopamine or cocaine abuse.